Role of Serotonin in Smypathetic Function

血清素在交感神经功能中的作用

基本信息

批准号：
7991763
负责人：
KARIE E SCROGIN
金额：
$ 25.99万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991763
关键词：
Acidosis Acute Address Adjuvant Age Agonist Animals Antihypertensive Agents Attenuated Bilateral Blood Blood Pressure Brain region Buffers Cardiac Cardiac Output Cardiovascular system Cause of Death Chemoreceptors Development Electric Capacitance Emergency Medicine Environmental air flow Financial compensation Health Hemorrhage Hemorrhagic Shock Hypercapnia Hypotension Hypovolemia Hypovolemic Shock Hypovolemics Individual Infusion procedures Injury Investigation Knockout Mice Lesion Maintenance Mediating Metabolic acidosis Methods Molecular Monitor Mus Nerve Neuraxis Neurons Norepinephrine Outcome Pathway interactions Patients Perfusion Plasma Process Rattus Receptor Activation Recovery Reperfusion Injury Respiratory Acidosis Resuscitation Role Serotonin Serotonin Receptor 5-HT1A Shock Splanchnic Nerves Techniques Testing Tissues Vasoconstrictor Agents Venous constriction extracellular hemodynamics hindbrain in vivo injured mouse model neuroregulation novel pre-clinical prevent receptor relating to nervous system research study respiratory response sensor serotonin receptor translational study vascular bed

项目摘要

DESCRIPTION (provided by applicant): This project will help to characterize the central nervous system mechanisms that regulate autonomic and respiratory compensation following hypovolemic hypotension and circulatory shock. Experiments will be conducted to test the hypothesis that caudal hindbrain serotonergic neurons activated by acidosis, stimulate 5-HT1A receptors to promote sympathetic-mediated venoconstriction of the splanchnic vascular bed during hypovolemia. It is further proposed that the preferential constriction of the venous vasculature induced by 5-HT1A receptor activation will produce less reperfusion injury during resuscitation from hypovolemic shock than clinically used vasoconstrictor agents which tend to constrict arterial vascular beds. Aim 1 will determine whether caudal hindbrain serotonin is critical for maintenance or recovery of sympathetic-mediated whole body venous tone and venous return following severe blood loss. Aim 2 will determine whether the acidemia associated with hypovolemia or respiratory and metabolic acidosis per se contribute to activation of caudal hindbrain serotonin neural activation and subsequent respiratory and autonomic responses. Further studies will assess with acidosis contributes to the maintenance of blood pressure through a preferential venoconstriction. Aim 3 will determine whether serotonin acts on 5-HT1A receptors to mediate compensatory responses to hypovolemia and whether this endogenous pathway can be exploited to produce a more favorable hemodynamic response during resuscitation from hypovolemic shock. These studies will rely heavily on a carefully developed in vivo rat and mouse models of hypotensive hemorrhage and hypovolemic shock. State of the art techniques for continuous monitoring of hemodynamic parameters, sympathetic nerve activity and central respiratory drive in unanesthetized animals will be used to assess cardiovascular parameters after pharmacological and molecular manipulation of serotonin and serotonin receptor levels. In addition, newly developed techniques for the recording of sympathetic activity in the unanesthetized mouse will enable use of genetically altered mice for investigation of the receptors involved in the compensatory responses to blood loss. Furthermore, novel molecular techniques to more acutely alter serotonin levels in discrete brain regions will be utilized to dissect regions important in the neural control of the circulatory responses to blood loss. Finally, pre-clinical, translational studies will address the potential utility of using 5-HT1A receptor agonists as adjuvants in resuscitation from circulatory shock. PUBLIC HEALTH RELEVANCE: Despite recent advances in emergency medicine, traumatic blood loss is currently one of the leading causes of death of individuals under 40 in the US. Patients typically succumb to severe blood loss either because of too little tissue perfusion or because of tissue injury incurred during the resuscitation process. Our studies will attempt to validate a new, promising therapy that may help patients recover from circulatory shock without further injuring tissue during the resuscitation process.

描述（由申请人提供）：该项目将有助于描述低血容量性低血压和循环性休克后调节自主神经和呼吸代偿的中枢神经系统机制。将进行实验来检验以下假设：酸中毒激活尾部后脑血清素能神经元，刺激 5-HT1A 受体，以促进低血容量期间交感神经介导的内脏血管床静脉收缩。进一步提出，与临床上使用的倾向于收缩动脉血管床的血管收缩剂相比，由5-HT1A受体激活诱导的静脉脉管系统的优先收缩将在低血容量性休克复苏期间产生更少的再灌注损伤。目标 1 将确定尾部后脑血清素对于维持或恢复交感神经介导的全身静脉张力和严重失血后的静脉回流是否至关重要。目标 2 将确定与血容量不足或呼吸和代谢性酸中毒相关的酸血症本身是否有助于激活尾部后脑血清素神经激活以及随后的呼吸和自主反应。进一步的研究将评估酸中毒是否有助于通过优先静脉收缩维持血压。目标 3 将确定血清素是否作用于 5-HT1A 受体以介导对低血容量的代偿反应，以及是否可以利用这种内源性途径在低血容量休克复苏期间产生更有利的血流动力学反应。这些研究将在很大程度上依赖于精心开发的体内大鼠和小鼠低血压出血和低血容量休克模型。在未麻醉动物中连续监测血流动力学参数、交感神经活动和中枢呼吸驱动的最先进技术将用于在对血清素和血清素受体水平进行药理学和分子操作后评估心血管参数。此外，新开发的记录未麻醉小鼠交感神经活动的技术将能够使用基因改造的小鼠来研究参与失血补偿反应的受体。此外，将利用新的分子技术来更敏锐地改变离散大脑区域的血清素水平，以剖析在失血循环反应的神经控制中重要的区域。最后，临床前转化研究将探讨使用 5-HT1A 受体激动剂作为循环休克复苏佐剂的潜在效用。公共卫生相关性：尽管急诊医学最近取得了进展，但创伤性失血目前仍是美国 40 岁以下人群死亡的主要原因之一。患者通常会因组织灌注过少或复苏过程中发生组织损伤而死于严重失血。我们的研究将尝试验证一种新的、有前途的疗法，该疗法可以帮助患者从循环性休克中恢复，而不会在复苏过程中进一步损伤组织。